July 2014
OECD GUIDELINE FOR THE TESTING OF CHEMICALS
DRAFT REVISED GUIDELINE 435:
In Vitro Membrane Barrier Test Method for Skin Corrosion
INTRODUCTION
1.
Skin corrosion refers to the production of irreversible damage to the skin, manifested as visible
necrosis through the epidermis and into the dermis, following the application of a test chemical [as defined
by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals
(GHS)] (1). A number of in vitro test methods have been proposed as alternatives for the standard in vivo
rabbit skin procedure (OECD TG 404)(2) used to identify corrosive substances. This Test Guideline is for
an in vitro membrane barrier test method that can be used to identify corrosive chemicals. The test method
utilizes an artificial membrane designed to respond to corrosive chemicals in a manner similar to animal
skin in situ.
2.
Skin corrosivity has traditionally been assessed by applying the test chemical to the skin of living
animals and assessing the extent of tissue damage after a fixed period of time (2)(3). The UN GHS tiered
testing and evaluation strategy for the assessment and classification of skin corrosivity and the OECD
Guidance document on Integrated Approaches to Testing and Assessment (IATA) for Skin
Irritation/Corrosion allows for the use of validated and accepted in vitro test methods under modules 3 and
4 (1) (18). This IATA provides guidance over several modules on (i) how to integrate and use existing the
test and non-test data for the assessment of the skin irritation and skin corrosion potentials of chemicals
(OECD, 2014) and (ii) proposes an approach when further testing is needed, including when negative
results are found. In this modular approach, positive results from in vitro test methods can be used to
classify a substance as corrosive without the need for animal testing, thus reducing and refining the use of
animals in testing. . The use of in vitro test methods to identify corrosive substances can therefore avoid
the pain and distress that might occur when animals are used for this purpose.
3.
Validation studies have been completed for an in vitro membrane barrier test method
commercially available as Corrositex® (4)(5)(6). Based on its acknowledged validity, this validated
reference test method (VRM) has been recommended for use as part of a tiered testing strategy for
assessing the dermal corrosion hazard potential of chemicals (5). Before an in vitro membrane barrier test
method for skin corrosion can be used for regulatory purposes, its reliability, relevance (accuracy), and
limitations for its proposed use should be determined to ensure that it is similar to that of the VRM
(7)(8)(9)(10), in accordance with the performance standards (PS) set out (19). The Mutual Acceptance of
Data will only be guaranteed after any proposed new or updated test method following the PS of this Test
Guideline have been reviewed and included in this Test Guideline.
4.
. Other test methods for skin corrosivity testing are based on the use of reconstituted human skin
(OECD TG 431)(11) and isolated rat skin (OECD TG 430)(12). This Test Guideline also provides for
subcategorisation of corrosive substances into the three GHS subcategories of corrosivity and the three UN
Transport Packing Groups for corrosivity hazard.
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DEFINITIONS
5.
Definitions used are provided in Annex 1.
INITIAL CONSIDERATIONS AND LIMITATIONS
6.
The test described in this Guideline allows the identification of corrosive chemicals and allows
the subcategorisation of corrosive chemicals as permitted in the GHS (Table 1)(1). In addition, such a test
method may be used to make decisions on the corrosivity and non-corrosivity of specific classes of
chemicals, e.g., organic and inorganic acids, acid derivatives1, and bases for certain transport testing
purposes (5)(13)(14). This Test Guideline describes a generic procedure similar to a validated reference
test method (5).
Table 1. The UN GHS Skin Corrosive Category and Subcategories (1)
Corrosive Category
(category 1)
(applies to authorities not
using subcategories)
Corrosive
Potential Corrosive
Subcategories
(only applies to some
authorities)
Corrosive in >1 of 3 animals
Exposure
Observation
Corrosive subcategory 1A
<3 minutes
<1 hour
Corrosive subcategory 1B
>3 minutes / <1 hour
<14 days
Corrosive subcategory 1C
>1 hour / <4 hours
<14 days
7.
A limitation of the validated reference test method (5) is that many non-corrosive chemicals and
some corrosive chemicals may not qualify for testing, based on the results of the initial compatibility test
(see paragraph 13). Aqueous chemicals with a pH in the range of 4.5 to 8.5 often do not qualify for testing;
however, 85% of chemicals tested in this pH range were non-corrosive in animal tests (5). The in vitro
membrane barrier test methods may be used to test solids (soluble or insoluble in water), liquids (aqueous
or non-aqueous), and emulsions. However, test chemicals not causing a detectable change in the
compatibility test ( i.e., colour change in the Chemical Detection System (CDS) of the validated reference
test method) cannot be tested with the membrane barrier test method and should be tested using other test
methods.
PRINCIPLE OF THE TEST
8.
The test system comprises two components: a synthetic macromolecular bio-barrier and a
chemical detection system (CDS); this test method detects via the CDS membrane barrier damage caused
by corrosive test substances after the application of the test chemical to the surface of the synthetic
macromolecular membrane barrier (5), presumably by the same mechanism(s) of corrosion that operate on
living skin.
9.
Penetration of the membrane barrier (or breakthrough) might be measured by a number of
procedures or CDS, including a change in the colour of a pH indicator dye or in some other property of the
indicator solution below the barrier.
1
“Acid derivative” is a non-specific class designation and is broadly defined as an acid produced from a chemical
substance either directly or by modification or partial substitution. This class includes anhydrides, halo acids, salts,
and other types of chemicals.
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10.
The membrane barrier should be determined to be valid, i.e., relevant and reliable, for its
intended use. This includes ensuring that different preparations are consistent in regard to barrier
properties, e.g., capable of maintaining a barrier to non-corrosive chemicals, able to categorize the
corrosive properties of chemicals across the various subcategories of corrosivity (1). The classification
assigned is based on the time it takes a chemical to penetrate through the membrane barrier to the indicator
solution.
DEMONSTRATION OF PROFICIENCY
Prior to routine use of the in vitro membrane barrier test method, adhering to this Test Guideline,
laboratories should demonstrate technical proficiency by correctly classifying the twelve Prociciency
Substances recommended in Table 2.
11.
Table 2: Proficiency Substances
Chemical
CASRN
Chemical Class
UN GHS
Subcategory*
Nitric acid
7697-37-2
Inorganic acids
1A
Phosphorus pentachloride
10026-13-8
Precursors of inorganic
acids
1A
Selenic acid
7783-08-6
Inorganic acids
1A
Valeryl chloride
638-29-9
Acid chlorides
1B
Sodium Hydroxide
1310-73-2
Inorganic bases
1B
1-(2-Aminoethyl) piperazine
140-31-8
Aliphatic amines
1B
Benzenesulfonyl chloride
98-09-9
Acid chlorides
1C
Hydroxylamine sulphate
10039-54-0
Organic ammonium salts
1C
Tetraethylenepentamine
112-57-2
Aliphatic amines
1C
Eugenol
97-53-0
Phenols
NC
2664-55-3
Acrylates/methacrylates
NC
Nonyl acrylate
Sodium bicarbonate
144-55-8
Inorganic salts
NC
The twelve substances listed above contain three substances from each of the three GHS subcategories for
corrosive substances and three non-corrosive substances, and are taken from the list of 40 reference
substancesthat are included in the minimum list of chemicals identified for demonstrating the accuracy and
reliability of test methods that are structurally and functionally similar to the validated reference test
method (see (5)(16)(19)). These chemicals are readily available from commercial suppliers, and the UN
GHS subcategory is based on the results of high-quality in vivo testing.
* The corresponding UN Packing groups are I, II and III, respectively, for the UN GHS Sub-categories 1A,
1B and 1C. NC; Non-corrosive.
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PROCEDURE
12.
The following is a generic description of the components and procedures of an artificial
membrane barrier test method for corrosivity assessment (7)(15). The membrane barrier and the
compatibility/indicator and categorisation solutions can be constructed, prepared or obtained
commercially, e.g., Corrositex®. A sample test method protocol for the validated reference test method
can be obtained at [http://iccvam.niehs.nih.gov]. Testing should be performed at ambient temperature (1725ºC) and the components should comply with the following conditions.
Test Substance Compatibility Test
13.
Prior to performing the membrane barrier test, a compatibility test is performed to determine if
the test chemical is detectable by the CDS. If the CDS does not detect the test chemical, the membrane
barrier test method is not suitable for evaluating the potential corrosivity of that particular test chemical
and a different test method should be used. The CDS and the exposure conditions used for the
compatibility test should reflect the exposure in the subsequent membrane barrier test.
Test Substance Timescale Category Test
14.
If appropriate for the test method, a test chemical that has been qualified by the compatibility test
should be subjected to a timescale category test, i.e., a screening test to distinguish between weak and
strong acids or bases. For example, in the validated reference test method a timescale categorization test is
used to indicate which of two timescales should be used based on whether significant acid or alkalai
reserve is detected. Two different breakthrough timescales should be used for determining corrosivity and
GHS skin corrosivity subcategory, based on the acid or alkali reserve of the test chemical.
Membrane Barrier Test Method Components
Membrane Barrier
15.
The membrane barrier consists in two components: a proteinaceous macromolecular aqueous gel
and a permeable supporting membrane. The proteinaceous gel should be impervious to liquids and solids
but can be corroded and made permeable. The fully constructed membrane barrier should be stored under
pre-determined conditions shown to preclude deterioration of the gel, e.g., drying, microbial growth,
shifting, cracking, which would degrade its performance. The acceptable storage period should be
determined and membrane barrier preparations not used after that period.
16.
The permeable supporting membrane provides mechanical support to the proteinaceous gel
during the gelling process and exposure to the test substance. The supporting membrane should prevent
sagging or shifting of the gel and be readily permeable to all test chemicals.
17.
The proteinaceous gel, composed of protein, e.g., keratin, collagen, or mixtures of proteins,
forming a gel matrix, serves as the target for the test chemical. The proteinaceous material is placed on the
surface of the supporting membrane and allowed to gel prior to placing the membrane barrier over the
indicator solution. The proteinaceous gel should be of equal thickness and density throughout, and with no
air bubbles or defects that could affect its functional integrity.
Chemical Detection System (CDS)
18.
The indicator solution, which is the same solution used for the compatibility test, should respond
to the presence of a test chemical. A pH indicator dye or combination of dyes, e.g., cresol red and methyl
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orange that will show a colour change, in response to the presence of the test chemical, should be used.
The measurement system can be visual or electronic.
19.
Detection systems that are developed for detecting the passage of the test chemical through the
barrier membrane should be assessed for their relevance and reliability in order to demonstrate the range of
chemicals that can be detected and the quantitative limits of detection.
TEST PERFORMANCE
Assembly of the Test Method Components
20.
The membrane barrier is positioned in a vial (or tube) containing the indicator solution so that the
supporting membrane is in full contact with the indicator solution and with no air bubbles present. Care
should be taken to ensure that barrier integrity is maintained.
Application of the Test Substance
21.
A suitable amount of the test chemical, e.g., 500 L of a liquid or 500 mg of a finely powdered
solid (5), is carefully layered onto the upper surface of the membrane barrier and evenly distributed. An
appropriate number of replicates, e.g., four (5), is prepared for each test chemical and its corresponding
controls. The time of applying the test substance to the membrane barrier is recorded. To ensure that short
corrosion times are accurately recorded, the application times of the test chemical to the replicate vials are
staggered.
Measurement of Membrane Barrier Penetrations
22.
Each vial is appropriately monitored and the time of the first change in the indicator solution, i.e.,
barrier penetration, is recorded, and the elapsed time between application and penetration of the membrane
barrier determined.
Controls
23.
In tests that involve the use of a vehicle or solvent with the test chemical, the vehicle or solvent
should be compatible with the membrane barrier system, i.e., not alter the integrity of the membrane
barrier system, and should not alter the corrosivity of the test chemical. When applicable, solvent (or
vehicle) control should be tested concurrently with the test chemical to demonstrate the compatibility of
the solvent with the membrane barrier system.
24.
A positive (corrosive) control with intermediate corrosivity activity, e.g., sodium hydroxide (UN
GHS Corrosive subcategory 1B) (7), should be tested concurrently with the test chemical to assess if the
test system is performing in an acceptable manner. A second positive control that is of the same chemical
class as the test substance may be useful for evaluating the relative corrosivity potential of a corrosive test
chemical. Positive control(s) should be selected that are intermediate in their corrosivity (e.g., UN GHS
subcategory 1B) in order to detect changes in the penetration time that may be unacceptably longer or
shorter than the established reference value, thereby indicating that the test system is not functioning
properly. For this purpose, extremely corrosive (UN GHS subcategory 1A) or non-corrosive chemicals are
of limited utility. A corrosive UN GHS subcategory 1B substance would allow detection of a too rapid or
too slow breakthrough time. A weakly corrosive (UN GHS subcategory 1C) might be employed as a
positive control to measure the ability of the test method to consistently distinguish between weakly
corrosive and non-corrosive chemicals. Regardless of the approach used, an acceptable positive control
response range should be developed based on the historical range of breakthrough times for the positive
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control(s) employed, such as the mean ± 2-3 standard deviations. In each study, the exact breakthrough
time should be determined for the positive control so that deviations outside the acceptable range can be
detected.
25.
A negative (non-corrosive) control, e.g., 10% citric acid, 6% propionic acid (7), should also be
tested concurrently with the test chemical as another quality control measure to demonstrate the functional
integrity of the membrane barrier.
Study Acceptability Criteria
26.
According to the established time parameters for each of the GHS corrosivity subcategories, the
time (in minutes) elapsed between application of a test chemical to the membrane barrier and barrier
penetration is used to predict the corrosivity of the test chemical. For a study to be considered acceptable,
the concurrent positive control should give the expected penetration response time, the concurrent negative
control should not be corrosive, and, when included, the concurrent solvent control should neither be
corrosive nor should it alter the corrosivity potential of the test chemical. Prior to routine use of a test
method that adheres to this Test Guideline, laboratories should demonstrate technical proficiency, using the
twelve chemicals recommended in Table 2. For new “me-too” test methods developed under this Test
Guideline that are structurally and functionally similar to the validated reference test method (16) the
performance standards should be used to demonstrate the reliability and accuracy of the new test method
prior to its use for regulatory testing (19).
Interpretation of Results and Corrosivity Classification of Test Substances
27.
The time (in minutes) elapsed between application of the test chemical to the membrane barrier
and barrier penetration is used to classify the test chemical in terms of corrosivity (1) and, if applicable,
UN Packing Group (17). Cut-off time values for each of the three corrosive subcategories are established
for each proposed test method. Final decisions on cut-off times should consider the need to minimize
under-classification of corrosive hazard ( i.e., false negatives).
DATA AND REPORTING
Data
28.
The time (in minutes) elapsed between application and barrier penetration for the test chemical
and the positive control(s) should be reported in tabular form as individual replicate data, as well as means
± the standard deviation for each trial.
Test Report
29.
The test report should include the following information:
Test Chemical
Mono-constituent substance:
- physical appearance, water solubility, and additional relevant physicochemical
properties;
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- chemical identification, such as IUPAC or CAS name, CAS number, SMILES or
InChI code, structural formula, purity, chemical identity of impurities as
appropriate and practically feasible, etc.
Multi-constituent substance, UVBCs and mixtures:
- characterised as far as possible by chemical identity (see above), quantitative
occurrence and relevant physicochemical properties of the constituents.
Control Substances:
– identification data and Chemical Abstracts Services Registry Number, if known;
– physical nature and purity (major impurities);
– physico-chemical properties relevant to the conduct of the study;
– treatment of the test/control substances prior to testing, if applicable, e.g., warming,
grinding;
– stability, if known.
Justification of the in vitro membrane barrier model and protocol used, including demonstrated
accuracy and reliability
Test Conditions:
– description of the apparatus and preparation procedures used;
– source and composition of the in vitro membrane barrier used;
– composition and properties of the indicator solution (;
– method of detection;
– test chemical and control substance amounts;
– number of replicates;
– description and justification for the timescale categorisation test;
– method of application;
– observation times.
Results:
– tabulation of individual raw data from individual test and control samples for each
replicate;
– descriptions of other effects observed;
– description of the evaluation and classification criteria.
Discussion of the results
Conclusions.
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LITERATURE
(1)
United Nations (UN) (2013). Globally Harmonized System of Classification and Labelling of
Chemicals (GHS), First revised edition, UN New York and Geneva, 2013. Available :
http://www.unece.org/trans/danger/publi/ghs/ghs_rev05/05files_e.html.
(2)
OECD (2002). Test Guideline 404. OECD Guideline for Testing of Chemicals. Acute Dermal
Irritation/Corrosion.
Updated
Guideline,
adopted
April
24,
2002.
Available:
[http://www.oecd.org/document/22/0,2340,en_2649_34377_1916054_1_1_1_1,00.html]
(3)
U.S. EPA 1998. Health Effects Test Guidelines: Acute Dermal Irritation. OPPTS 870.2500.
Washington, DC. U.S. Environmental Protection Agency. Available:
[http://www.epa.gov/docs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/
870-2500.pdf]
(4)
Fentem, J.H., Archer, G.E.B., Balls, M., Botham, P.A., Curren, R.D., Earl, L.K., Esdaile, D.J.,
Holzhutter, H.-G. and Liebsch, M. (1998). The ECVAM international validation study on in vitro tests for
skin corrosivity. 2. Results and evaluation by the management team. Toxicology In Vitro 12, 483-524.
(5)
ICCVAM (1999). Corrositex®. An In Vitro Test Method for Assessing Dermal Corrosivity
Potential of Chemicals. The Results of an Independent Peer Review Evaluation Coordinated by ICCVAM,
NTP
and
NICEATM.
NIEHS,
NIH
Publication
No.
99-4495.
Available
at
[http://iccvam.niehs.nih.gov/docs/reports/corprrep.pdf], together with a Sample Protocol for the
Corrositex® test kit at [http://iccvam.niehs.nih.gov/methods/corrdocs/sampprot.pdf]
(6)
Gordon, V.C., Harvell, J.D. and Maibach, H.I. (1994). Dermal Corrosion, the Corrositex®
System: A DOT Accepted Method to Predict Corrosivity Potential of Test Materials. In vitro Skin
Toxicology-Irritation, Phototoxicity, Sensitization. Alternative Methods in Toxicology 10, 37-45.
(7)
ICCVAM (1997). Validation and Regulatory Acceptance of Toxicological Test Methods. A
Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods.
NIEHS,
NIH
Publication
No.
97-3981.
Available:
[http://iccvam.niehs.nih.gov/docs/guidelines/validate.pdf]
(8)
OECD (1996). Report of the OECD Workshop on “Harmonisation of Validation and Acceptance
Criteria for Alternative Toxicological Test Methods”. Paris, 1996, (Solna Report) [ENV/MC/CHEM(96)9]
(9)
OECD (2002). Report of the Stockholm Conference on “Validation and Regulatory Acceptance
of New and Updated Methods in Hazard Assessment”. Paris, 2002 [ENV/JM/TG/M(2002)2]
(10)
Balls, M. and Karcher, W. (1995). Comment: The Validation of Alternative Test Methods.
ATLA 23:884-886.
(11)
OECD (2004). Test Guideline 431. OECD Guideline for Testing of Chemicals. In Vitro Skin
Corrosion: Human Skin Model Test.
Available: [http://www.oecd.org/document/22/0,2340,en_2649_34377_1916054_1_1_1_1,00.html]
(12)
OECD (2004). Test Guideline 430. OECD Guideline for Testing of Chemicals. In Vitro Skin
Corrosion: Transcutaneous Electrical Resistance Test (TER).
Available: [http://www.oecd.org/document/22/0,2340,en_2649_34377_1916054_1_1_1_1,00.html]
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435
(13)
ECVAM (2001). Statement on the Application of the CORROSITEX Assay for Skin
Corrosivity Testing. 15th Meeting of ECVAM Scientific Advisory Committee (ESAC), Ispra, Italy.
ATLA 29(2), 96-97.
(14)
U.S. DOT (2002). Exemption DOT-E-10904 (Fifth Revision). September 20, 2002. Washington,
D.C., U.S. DOT. Available: [http://hazmat.dot.gov/exemptions/E10904.pdf]
(15)
U.S. EPA (1996). Method 1120, Dermal Corrosion.
Available: [http://www.epa.gov/epaoswer/hazwaste/test/pdfs/1120.pdf]
(16)
ICCVAM (2004). ICCVAM Recommended Performance Standards for In Vitro Test Methods for
Skin
Corrosion.
NIEHS,
NIH
Publication
No.
04-4510.
Available:
[http://iccvam.niehs.nih.gov/methods/epiderm.htm]
(17)
United Nations (UN) (2003).Recommendations of the Transport of Dangerous Goods, Model
Regulations, 13rd revised edition, ST/SG/AC.10/1/Rev.13 (Vol. I), UN New York and Geneva,
2003.Available : http://www.unece.org/trans/danger/publi/unrec/rev13/13files_e.html.
(18)
Guidance Document on Integrated Approaches to Testing and Assessment of Skin
Irritation/Corrosion, Series on Testing and Assessment, No. 203, OECD, Paris.
(19)
Performance Standards for proposed in vitro membrane barrier test method for skin corrosion in
TG 435, Series on Testing and Assessment, No. XXX, OECD, Paris.
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ANNEX 1
DEFINITIONS
Accuracy: The closeness of agreement between test method results and accepted reference values. It is a
measure of test method performance and one aspect of relevance. The term is often used interchangeably
with “concordance” to mean the proportion of correct outcomes of a test method. (7)(8)(10).
Chemical Detection System (CDS): A visual or electronic measurement system with an indicator
solution that responds to the presence of a test substance, e.g., by a change in a pH indicator dye, or
combination of dyes, that will show a colour change in response to the presence of the test substance or by
other types of chemical or electrochemical reactions.
False negative rate: The proportion of all positive substances falsely identified by a test method as
negative Its one indicator of test method performance.
False positive rate: The proportion of all negative (non-active) substances that are falsely identified as
positive. It is one indicator of test performance.
GHS: (Globally Harmonized System of Classification and Labelling of Chemicals): a system proposing
the classification of chemicals (substances and mixtures) according to standardized types and levels of
physical, health and environmental hazards, and addressing corresponding communication elements, such
as pictograms, signal words, hazard statements, precautionary statements and safety data sheets, so that to
convey information on their adverse effects with a view to protect people (including employers, workers,
transporters, consumers and emergency responders) and the environment (1).
Inter-laboratory reproducibility: A measure of the extent to which different qualified laboratories, using
the same protocol and testing the same substances, can produce qualitatively and quantitatively similar
results. Inter-laboratory reproducibility is determined during the prevalidation and validation processes,
and indicates the extent to which a test can be successfully transferred between laboratories, also referred
to as between-laboratory reproducibility.
Performance standards: Standards, based on a validated test method, that provide a basis for evaluating
the comparability of a proposed test method that is mechanistically and functionally similar. Included are
(1) essential test method components; (2) a minimum list of reference chemicals selected from among the
chemicals used to demonstrate the acceptable performance of the validated test method; and (3) the
comparable levels of accuracy and reliability, based on what was obtained for the validated test method,
that the proposed test method should demonstrate when evaluated using the minimum list of reference
chemicals.
Reference chemicals: Chemicals selected for use in the validation process, for which responses in the in
vitro or in vivo reference test system or the species of interest are already known. These chemicals should
be representative of the classes of chemicals for which the test method is expected to be used, and should
represent the full range of responses that may be expected from the chemicals for which it may be used,
from strong, to weak, to negative. Different sets of reference chemicals may be required for the different
stages of the validation process, and for different test methods and test uses.
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Relevance: Description of relationship of the test to the effect of interest and whether it is meaningful and
useful for a particular purpose. It is the extent to which the test correctly measures or predicts the
biological effect of interest. Relevance incorporates consideration of the accuracy (concordance) of a test
method. (7)(8)(10).
Reliability: Measures of the extent that a test method can be performed reproducibly within and between
laboratories over time, when performed using the same protocol. It is assessed by calculating intra- and
inter-laboratory reproducibility and intra-laboratory repeatability.
(7)(8)(10).
Sensitivity: The proportion of all positive/active substances that are correctly classified by the test. It is a
measure of accuracy for a test method that produces categorical results, and is an important consideration
in assessing the relevance of a test method.
Specificity: The proportion of all negative/inactive substances that are correctly classified by the test. It is
a measure of accuracy for a test method that produces categorical results and is an important consideration
in assessing the relevance of a test method.
Skin corrosion in vivo: The production of irreversible damage of the skin; namely, visible necrosis
through the epidermis and into the dermis, following the application of a test chemical for up to four hours.
Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at
14 days, by discoloration due to blanching of the skin, complete areas of alopecia, and scars.
Histopathology should be considered to evaluate questionable lesions.
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